PROJECT SUMMARY Increasing evidence suggests that while poor meal timing can cause cardiometabolic disease, optimized meal timing may reverse it. Time-restricted feeding (TRF) is a novel type of intermittent fasting that involves eating within a ?10-hour period, followed by a ?14 hour daily fast. Studies in rodents report that TRF improves glycemic control, lowers insulin levels, reduces hepatic fat, prevents hyperlipidemia, reduces infarct volume after stroke, and improves inflammatory markers, relative to eating throughout the day. Importantly, the effects of TRF may depend on the circadian timing of food intake. Previous TRF trials in humans that limited food intake to the middle of the daytime (mid-day TRF) reported positive results, while trials that limited food intake to late in the day reported null or negative results. Building on these studies, we recently conducted the first clinical trial of TRF where food intake is limited to early during the daytime (early TRF) and found that five weeks of early TRF improved insulin sensitivity, ?-cell responsiveness, blood pressure, and oxidative stress in prediabetic men? even though food intake was matched to the control arm and no weight loss occurred. Here, we propose to conduct both (1) the first full-scale trial of TRF in humans and (2) the first trial to determine whether the effects of TRF depend on the circadian timing of food intake. Our proposed study is a three-parallel-arm, controlled feeding trial designed to determine the efficacy of TRF as a therapy to improve cardiometabolic health in prediabetic adults. N=144 prediabetic adults (BMIs 25-50 kg/m2; aged 18-75 years old) will be randomized to one of three isocaloric eating schedules: (1) early TRF: 6-hour feeding interval from 8 am-2 pm; (2) mid-day TRF: 6-hour feeding interval from 2 pm-8 pm; and (3) control schedule: 12-hour eating interval from 8 am-8 pm. For 10 weeks, participants will eat calorie-matched meals under remote supervision by video monitoring, and food intake will be precisely matched on a meal-by-meal basis to the control group to ensure that no weight loss occurs. The study endpoints will be measured during a 24-hour inpatient test period at both baseline and post- intervention. The primary endpoint is 24-hour glycemic control as measured by 24-hour mean values of glucose and insulin; this data will be complemented by mechanistic data on insulin sensitivity and secretion, as measured by three identical meal tolerance tests on the same day. The secondary endpoints are cardiovascular disease risk factors, as measured by 24-hour blood pressure and fasting levels of lipids and inflammatory and oxidative stress markers. We hypothesize that both TRF schedules will improve cardiometabolic health, but the effects of TRF will depend on the circadian timing of food intake, with the order of improvements being early TRF > mid- day TRF > control. This study will provide critical insight into (1) whether TRF can be used to treat metabolic disease; (2) the relative importance of the length of the daily fasting period (intermittent fasting) versus the circadian timing of food intake (meal timing) for metabolic health; and (3) whether breakfast skipping (tantamount to mid-day TRF) is beneficial or detrimental for metabolic health when dinner time is unchanged.